Project Summary The Zika virus (ZIKV) causes severe birth defects such as microcephaly. The WHO has declared the Zika virus disease as a global public health emergency. However, developing safe and efficient preventive and therapeutic vaccines for it may take many years and is very expensive. Here, we propose to develop a novel platform called ?chemical intravenous- immunoglobulins? (CIVIG) for rapid generation of therapeutic/prophylactic antisera against ZIKV. In the CIVIG platform, we will introduce high-affinity and high-specificity ligands against the virus to the native immunoglobulins isolated from normal donors, converting them into microbe- specific antisera. This revolutionary platform is based on our recently published method to site- specifically ligate the microbe capturing ligands to the indole binding site (IBS) at Fab region of clinical grade intravenous-immunoglobulins (IVIG). The resulting ligand-decorated polyclonal antiserum is expected to bind to and neutralize the causative microbial agent. In this project, high-affinity and high-specificity ligands against ZIKV envelope protein and intact Zika virions will be discovered and optimized via the enabling one-bead-one-compound (OBOC) combinatorial chemical library technology. The ligands identified will be evaluated for cross- reactivity with other related flaviviruses (e.g., Dengue virus). Such ligands will be site-specifically ligated to the Fab region of IVIG with IBS-affinity element, via proximity ligation, to form CIVIG. The binding affinity and specificity of the CIVIGs to Zika virion will be determined with surface plasmon resonance (SPR). In vitro neutralizing effects of CIVIGs will be tested in Vero cells and primary human skin cells (e.g. normal human fibroblasts). Antibody-dependent enhancement (ADE) of virus infection and cytotoxicity will also be tested using cell-based established protocols prior to in vivo testing of CIVIG. The proposed platform is highly versatile, efficient, economical, and the time it takes from ligand discovery to scale up production of neutralizing antisera can be as short as three months. This general platform technology can be further applied for other emerging infectious diseases and modified for screenings using non-infectious virus-like particle and/or purified viral envelope proteins.